Zhou Yong, Liu Tian, Duan Jia-Xi, Li Ping, Sun Guo-Ying, Liu Yong-Ping, Zhang Jun, Dong Liang, Lee Kin Sing Stephen, Hammock Bruce D, Jiang Jian-Xin, Guan Cha-Xiang
*Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China †Department of Physiology, Hunan University of Medicine, Huaihua, Hunan China ‡Department of Anesthesiology, Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou China §Department of Entomology and the UC Davis Cancer Center, University of California Davis, Davis, California ||State Key Laboratory of Trauma, Burns, and Combined Injury, Research Institute of Surgery, Daping Hospital, Third Military Medical University, Chongqing, Sichuan, China.
Shock. 2017 May;47(5):638-645. doi: 10.1097/SHK.0000000000000767.
Acute lung injury (ALI) is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production leading to lung edema. The mortality rate of patients suffering from ALI remains high. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of polyunsaturated fatty acid with antihypertensive, profibrinolytic, and anti-inflammatory functions. EETs are rapidly hydrated by soluble epoxide hydrolase (sEH) to their less potent diols. The aim of this study was to investigate the role of sEH inhibitor trifluoromethoxyphenyl propionylpiperidin urea (TPPU) and EETs in lipopolysaccharide (LPS)-induced ALI of mice. Our studies revealed that inhibition of sEH with TPPU attenuated the morphological changes in mice, decreased the neutrophil infiltration to the lung, pro-inflammatory cytokine levels (IL-1β and TNF-α) in serum and bronchoalveolar lavage fluid (BALF), and alveolar capillary leakage (lung wet/dry ratio and total protein concentration in BALF). TPPU improved the survival rate of LPS-induced ALI. In addition, in vitro experiments revealed that both TPPU and EETs (11,12-EET and 14,15-EET) suppressed the expression of IL-1β and TNF-α, and LDH release in RAW264.7 cells. These results indicate that EETs play a role in dampening LPS-induced acute lung inflammation, and suggest that sEH could be a valuable candidate for the treatment of ALI.
急性肺损伤（ALI）的特征为肺泡迅速损伤、血管渗漏、肺部炎症、中性粒细胞积聚以及诱导细胞因子产生，进而导致肺水肿。ALI患者的死亡率仍然很高。环氧二十碳三烯酸（EETs）是细胞色素P450依赖的多不饱和脂肪酸衍生物，具有抗高血压、促纤溶和抗炎功能。EETs可被可溶性环氧化物水解酶（sEH）迅速水合为活性较低的二醇。本研究旨在探讨sEH抑制剂三氟甲氧基苯基丙酰哌啶脲（TPPU）和EETs在脂多糖（LPS）诱导的小鼠ALI中的作用。我们的研究表明，用TPPU抑制sEH可减轻小鼠的形态学变化，减少中性粒细胞向肺内浸润、血清和支气管肺泡灌洗液（BALF）中促炎细胞因子水平（IL-1β和TNF-α）以及肺泡毛细血管渗漏（肺湿/干比和BALF中总蛋白浓度）。TPPU提高了LPS诱导的ALI小鼠的存活率。此外，体外实验表明，TPPU和EETs（11,12-EET和14,15-EET）均抑制RAW264.7细胞中IL-1β和TNF-α的表达以及乳酸脱氢酶（LDH）释放。这些结果表明，EETs在减轻LPS诱导的急性肺部炎症中发挥作用，并提示sEH可能是治疗ALI的一个有价值的候选靶点。
